Rheumatoid arthritis (RA) is a systemic disease of unknown etiology that occurs predominantly in women. The progressive joint destruction associated with RA is mediated by a complex inflammatory tissue called pannus that is composed of macrophages, fibroblasts, synoviocytes, and blood vessels. Secreted proteins called cytokines control the formation and function of pannus. Specific cytokines that are believed to play a role in mediating the inflammation of RA include TNFα, IL-1β, and IL-6.
P38α MARK is an enzyme important to the intracellular signaling pathway for the generation of TNFα and IL-1b. Multiple extracellular stimuli including stress signals such as lipopolysaccharide, osmotic or heat shock, and pro-inflammatory cytokines such as TNFα, IL-1β stimulate the P38 pathway. Activation of the P38α pathway causes both transcriptional and translation modulation of gene expression of TNFα, IL-1β that is both cell type and signal specific.
Biological agents that selectively neutralize pro-inflammatory cytokines (tumor necrosis factor such as TNFα and interleukin [IL]-1β) have been shown to reduce the number of swollen and tender joints and to retard the destruction of joint tissue. P38 inhibitors of the pyridinylimadazole class block the destruction of joint tissue and the production of the TNFα and IL-1β in monocytes and in animal models of arthritis. Currently, there are no marketed, orally active, safe and effective agents that act primarily to inhibit TNFα or IL-1β. 6-(2,4-difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)-propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidine-7-one (1) is being developed as an oral agent that will suppress IL-1β, TNFα, and related cytokine production, with the potential to provide increased safety and efficacy compared to the current standard oral therapies for RA.
International patent publications; WO 02/18379 (A2), WO 01/29401 (A1), and WO 02/064594 (A2) and U.S. Patent Application Publication 2005/0107408 (A1) disclose methods for the preparation of 6-(2,4-difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)-propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidine-7-one (1) and its use for the treatment of P38 mediated disorders.
6-(2,4-difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)-propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidine-7-one (1) can be prepared by coupling 3-amino-pentan-1,5-diol (2) and a sulfone intermediate (3) as shown below in Scheme 1:

One of the key intermediates for preparing compound (1) is 3-amino-pentan-1,5-diol (2). Several synthetic routes for preparing intermediate (2) have been disclosed in the literature (Helvetica Chimica Acta, vol. 8, page 2145-2155 (1964), and in copending U.S. Provisional Patent Application No. 60/876,828. These synthetic routes have the shortcomings of high manufacturing costs, environmental impact, and technical difficulties for commercial scale manufacturing.
In the literature method (Helvetica Chimica Acta, vol. 8, page 2145-2155 (1964)) the 3-amino-pentan-1,5-diol (2) (shown in Scheme 2) is prepared via the lithium aluminum hydride (LAH) reduction of unprotected diethyl-3-amino-glutarate HCl salt (4).

The diethyl-3-amino-glutarate HCl salt (4) is prepared following the literature procedure (J. Amer. Chem. Soc. vol. 77, page 5427 (1955)). The isolation of the water soluble 3-amino-pentan-1,5-diol (2) from the aluminum salts is very difficult and results in poor yields. Handling LAH on a large scale is hazardous.
Another process for the production of 3-amino-pentan-1,5-diol (2) is described in U.S. Provisional Patent Application No. 60/876,828 and shown in Scheme 3.

Reduction of de-benzylated dimethyl-3-N-benzylamino-glutarate (6) followed by aqueous workup results in poor recovery of 3-amino-pentan-1,5-diol (2). Very good recovery of 3-N-benzylamino-petan-1,5-diol (7) achieved from the aqueous workup after the reduction of dimethyl-3-N-benzylamino-glutarate (6). The 3-N-benzylamino-petan-1,5-diol (7) is not soluble in water hence the extraction from the aluminum salts is quite facile. The 3-N-benzylamino-petan-1,5-diol (7) is purified via crystalline tosylate salt. The final deprotection of the benzyl group to obtain 3-amino-pentan-1,5-diol (2) was possible under non-aqueous condition.
Reduction of the dimethyl-3-N-benzylamino-glutarate (6) to the 3-N-benzylamino-petan-1,5-diol (7) can be accomplished in two methods. One method employs sodium borohydride, which is inexpensive. This method requires a long reaction time, e.g. 72 hours, and results in an impurity that is difficult to remove from the down stream process. An alternative method employs a toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride (vitride), an easily scalable reducing agent. The recovery of the benzyl protected 3-N-benzyl-amino-pentane-1,5-diol (7) from the aluminum salts after vitride reduction requires multiple, e.g. five or six, extractions with dichloromethane solvent. Formation of a crystalline tosylate salt of the aminodiol eliminates the need for distillation. This process, starting from dimethyl-3-N-benzylamino-glutarate (6), has an overall yield of 69%.